San Diego Team Asthma Management using Phenotypes (STAMP)

圣地亚哥团队使用表型进行哮喘管理 (STAMP)

• 批准号: 9981490
• 负责人: Praveen Akuthota
• 金额: $ 39.84万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-23 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981490
• 关键词: Adrenal Cortex Hormones; Adrenergic Agents; Adult; Affect; Allergic Disease; American; Asthma; Biological; Biological Markers; Biological Products; Biological Response Modifier Therapy; Blood; Blood specimen; California; Cellular Assay; Childhood; Clinical; Clinical Management; Clinical Research; Clinical Trials; Clinical Trials Design; Clinical Trials Network; Development; Disease; Eosinophilia; Etanercept; Exhalation; Failure; Future; Genomics; Goals; Grant; Heterogeneity; Hypersensitivity; IL4 gene; IgE; Immune; Immunology; Inflammation; Inhalation; Institutes; Interleukin-13; Interleukin-4; Interleukin-5; Intervention; Investigational Therapies; Leukotrienes; Modification; Monoclonal Antibodies; Monoclonal Antibody R24; National Heart, Lung, and Blood Institute; New Agents; Patients; Pharmaceutical Preparations; Phase; Phenotype; Placebos; Process; Protocols documentation; Pulmonology; Randomized; Research Institute; Resources; Sampling; Serum; Sputum; Stratification; Study Subject; Surface; TNF gene; Therapeutic; Translational Research; Universities; Work; anti-IgE; arm; asthma exacerbation; asthmatic patient; base; clinical center; design; drug development; eosinophil; epigenomics; individual patient; inhibitor/antagonist; interest; interleukin-13 receptor; interleukin-5 receptor; mepolizumab; novel marker; novel strategies; novel therapeutics; omalizumab; periostin; personalized intervention; primary outcome; programs; receptor; recruit; response; sialic acid binding Ig-like lectin; success; targeted treatment; tool; treatment response; trial design

Project Summary/Abstract There has been increasing recognition over the last several years of the heterogeneity in the pathobiologic underpinnings of asthma and the critical importance of phenotyping and endotyping in dictating response to therapy. For example, it was only after selecting patients with sputum (and later blood) eosinophilia and using exacerbation rate as the primary outcome, was the utility of mepolizumab in asthma uncovered in a clinical trial setting. With multiple immune-modulating biologic agents already available and with more to come in the very near future, our understanding how to best deploy these agents in a precise manner to patients with severe and/or exacerbation-prone asthma (those who would be most likely to be prescribed biologic agents) must be refined. The PrecISE Network will use sequential, adaptive clinical trial designs, which represents a novel approach in asthma clinical research, to answer these questions, while also presenting an opportunity for significant progress in phenotyping and endotyping as applied to clinical management of patients with severe asthma. In this application, we propose the following Specific Aims: 1) Establishment of the San Diego Team Asthma Management Program (STAMP) as a Clinical Center in the NHLBI PrecISE Network: We have put together a team that leverages the substantial resources of UCSD and the San Diego region to create a PreCISE Clinical Center that will optimally recruit subjects and perform PrecISE Network protocols as they are developed and implemented. 2) Proposal of a PrecISE Netowrk Clinical Trial Using a sequential, adaptive, phase IIb/proof of concept design: In accordance with the goals of the PrecISE Network, our proposed trial design will be center on the use of precision interventions based on stratification of severe asthma subjects by phenotype/endotype. Using already established biomarkers, including blood/sputum eosinophilia, serum periostin, serum IgE, and exhaled NO, we propose to stratify subjects into Th2-high (“Th2H”), non-Th2-high (“NTh2H”), and MIXED endotypes to dictate experimental interventions. Th2H and MIXED subjects would be randomized to placebo, Allakos (Anti-Siglec-8 monoclonal antibody), or dupilumab (anti-IL4/IL13 receptor). Concurrently, NTh2H subjects would be randomized into placebo, etanercept (TNF inhibitor), or dupilumab. During the trial, some of these interventions may be shown to have a lack of sufficient activity and these will be withdrawn after interim analysis and replaced by new agents or by new biomarker-defined groups. Successful treatments at the interim analysis stage will proceed to the next stage. 3) Identification of novel biomarkers to stratify responders to targeted treatments: Our group has the scientific expertise to perform and analyze novel biomarker studies associated with PrecISE protocols. We propose to leverage these micro-scaled genomic and immunology tools to identify novel biomarkers for treatment response from sputum and blood samples of our study subjects.

项目概要/摘要 在过去的几年里，人们越来越认识到病理生物学的异质性。 哮喘的基础以及表型和内型分析在决定哮喘反应中的至关重要性 例如，只有在选择痰液（后来是血液）嗜酸性粒细胞增多的患者并使用后才进行治疗。 恶化率作为主要结局，是临床试验中发现的美泊利单抗在哮喘中的效用 目前已有多种免疫调节生物制剂可用，并且即将推出更多免疫调节生物制剂。 在不久的将来，我们将了解如何以精确的方式最好地将这些药物部署到重症患者身上 和/或易恶化的哮喘（那些最有可能服用生物制剂的人）必须 PrecISE 网络将采用连续的、适应性的临床试验设计，这代表了一种新颖的方法。 哮喘临床研究的方法，回答这些问题，同时也提供了一个机会 表型和内型分析应用于重症患者的临床管理方面取得了重大进展 在本申请中，我们提出以下具体目标： 1) 建立圣地亚哥团队。 哮喘管理计划 (STAMP) 作为 NHLBI PrecISE 网络中的临床中心：我们已将 一个团队利用加州大学圣地亚哥分校和圣地亚哥地区的大量资源共同创建了一个 PrecISE 临床中心将优化招募受试者并按原样执行 PrecISE 网络协议 2) 使用连续的、适应性的、PrecISE Netowrk 临床试验的提案。 IIb 阶段/概念设计验证：根据 PrecISE Network 的目标，我们提出的试验 设计的重点是使用基于严重哮喘受试者分层的精准干预措施 使用已经建立的生物标志物，包括血液/痰嗜酸性粒细胞增多、血清。 根据骨膜素、血清 IgE 和呼出气 NO，我们建议将受试者分为 Th2 高（“Th2H”）和非 Th2 高 （“NTh2H”）和混合内型来决定实验干预。 随机分配至安慰剂、Allakos（抗 Siglec-8 单克隆抗体）或 dupilumab（抗 IL4/IL13 受体）。 同时，NTh2H 受试者将被随机分为安慰剂、依那西普（TNF 抑制剂）或 dupilumab。 在试验期间，其中一些干预措施可能被证明缺乏足够的活性，这些干预措施将被 中期分析后撤回，并由新药物或新生物标志物定义的成功组取代。 中期分析阶段的治疗将进入下一阶段 3) 鉴定新的生物标志物。 对针对性治疗的反应者进行分层：我们的团队拥有执行和分析新颖药物的科学专业知识 我们建议利用这些微型基因组进行与 PrecISE 协议相关的生物标志物研究。 和免疫学工具，用于从痰和血液样本中识别治疗反应的新型生物标志物 我们的研究课题。